Lymphoid homeostasis is maintained by the dynamic regulation of lymphocyte activation, proliferation, programmed cell death, and tissue specific homing. Negative regulators of lymphoid homeostasis, including Fas, interleukin-2 receptor alpha (IL-2Ralpha), and CTLA-4 have been identified by analyses of mutant mice lacking these molecules. These mice accumulate large numbers of activated lymphocytes and develop autoimmune disease. Positive regulators of lymphoid homeostasis should maintain the number and activation state of T lymphocytes in vivo. Such proteins are central to the issue of human immune responses are sustained in vivo and how memory cells are generated and maintained over long periods of time. The interleukin-15 (IL-15) receptor alpha chain (IL-15Ralpha) mediates high affinity binding of IL-15, a pleiotropic cytokine which resembles IL-2 and is thought to support lymphocyte activation and survival. As the functions of IL-15Ralpha in immune regulation are unknown, we have generated IL-15Ralpha deficient (IL-15Ralpha-/-) mice. These mice possess few activated lymphocytes and are lymphopenic-particularly in intestinal tissues which would normally harbor such cells. The provocative phenotype of these mice provides the first direct evidence of a signal which maintains activated T lymphocytes in vivo. These findings also suggest that IL-15Ralpha may sustain the duration of immune responses and support memory cells in vivo. Accordingly, we propose in this application to use these novel mice to investigate the mechanism(s) by which IL-15Ralpha regulates lymphoid homeostasis in vivo. We will study the capacity of IL-15Ralpha-/- lymphocytes to proliferate, resist programmed cell death, and migrate to lymphoid and non-lymphoid tissues. We will then study the role of IL-15Ralpha in immune responses. Finally, we will investigate the role of IL-15Ralpha in sustaining the survival of resting and activated lymphocytes in vivo. These experiments will reveal how IL-15Ralpha positively supports lymphoid homeostasis and determine how IL-15Ralpha regulates immunological memory.